Ether preservation



United States Patent 25,818,438 lcfi Patented Dec. 31, 1957 ETHER PRESERVATION Edward Mallinckrodt, In, St. Louis, and Archie E. Ruelile, Kirkwootl, Mo., assignors to Mallinckrodt Chemical Works, St. Louis, Mo., a corporation of Missouri N Drawing. Application April 28, 1954 Serial No. 426,290

13 Claims. (Cl. 260-6115) This invention relates to ether preservation, and more particularly to the preservation of ether by means of certain dimethyldithiocarbamate and diethyldithiocarbamate preservative compounds.

Briefly, this invention relates to a composition comprising a substantial proportion of ether and a preservative compound selected from the group consisting of cupric dimethyldithiocarbamate, cupric diethyldithiocarbamate, sodium dimethyldithiocarbamate, sodium diethyldithiocarbamate, stannous dimethyldithiocarbamate and stannous diethyldithiocarbamate. The invention also relates to the method of preserving ether which comprises dissolving therein a perservative compound selected from the above-noted group.

Among the objects of the invention may be noted the provision of improved means of preserving ether against decomposition; the provision of such means which are effective in minute quantities to preserve ether; and the provision of means of the character described which preserve ether for relatively long periods of time. Other objects and features will be in part apparent and in part pointed out hereinafter.

The invention accordingly comprises the products and methods hereinafter described, the scope of the invention being indicated in the following claims.

Diethyl ether in untreated tin cans, within a short time following its manufacture, may acquire sufficient decomposition products to make it fail to pass the United States Pharmacopoeias rigorous requirements for ether intended for anesthesia. In recognition of these properties of ether, the Pharmacopoeia requires that ether for anesthesia be packed in tight containers of not more than 3 kg. capacity and that it be used within twenty-four hours after removal from the original container. Peroxide and aldehyde impurities are particularly objectionable in anesthetic ether, and indeed are limited to the merest traces by the specification of the United States Pharmacopoeia. Once started, the formation of peroxides may increase through auto-oxidation. Heat, light, air and catalytically active surfaces inside the container influence the formation of ether peroxides. The efiects of these factors on the formation of peroxide impurities may be considerably minimized by forming on the cans inner surface an adherent layer of tin oxide or a coating of metallic copper. Such expedients, however, are not entirely satisfactory. The best results have been obtained with a container having a copper-tin oxide coating on the inside surface, as described and claimed in our U. S. Patent No. 2,587,744, issued March 4, 1952. Another expedient which has been employed is the addition of a preservative to the ether which prevents or inhibits peroxide formation. Hydroquinone and diphenylamine are well-known preservatives; but these compounds possess only limited usefulness.

In accordance with the present invention, certain dimethyldithiocarbamate and diethyldithiocarbamate metal organic complexes have been found which exhibit an improved preserving action on ether. When dissolved in ether in minute amounts, they are effective in preventing, inhibiting or delaying the formation of peroxides, thereby prolonging the keeping time of ether following manufacture. The use of these preservative compounds in conjunction with treated or coated containers, such as mentioned above, is particularly advantageous and considerably increases the stability of ether in storage. The particular dimethyldithiocarbamate and diethyldithiocarbamate salts which have been found elfective in preserving ether are the cupric, sodium and stannous salts.

The dimethyldithiocarbamate and diethyldithiocarba mate preservative compounds of this invention are more effective than hydroquinone to increase the keeping time of ether even at concentrations one-tenth to one-hundredth that of hydroquinone. All the compounds of the present invention exhibit improved preserving action at a concentration of only 10- molar or less when compared with hydroquinone at ten times this concentration (10* molar). Furthermore, when employed in conjunction with treated containers having an interior adherent coating of copper-tin oxide or lacquer varnish, still smaller concentrations of these preservative compounds are effective as the following illustrative examples will demonstrate.

Example I The preservative action of these compounds upon ether was demonstrated by an accelerated aging test of the compositions of the present invention under conditions which favor the rapid spoilage of ether, i. e., contact with a polished tin surface and shaking it at a temperature of F. for sixteen hours. The preservatives to be tested were dissolved in freshly distilled anhydrous (absolute) ether, initially containing less than 0.05 p. p. m. peroxide and less than 2-3 p. p. m. aldehyde, and made up to the desired concentration. By this test, the relative effectiveness of various preservatives and other methods of preserving ether can be determined.

At the end of the sixteen-hour test period the ether was tested for the amount of peroxide and aldehyde it contained. If the sample was found to contain more than 0.2 part per million peroxide (the U. S. P. limit corresponds to about 0.5 p. p. m.) or over 3 p. p. m. aldehyde as acetaldehyde (the U. S. P. limit corresponds to slightly over 13 p. p. m.) it was considered to have failed in the test. In carrying out the tests, the preservative is added to 18 ml. of freshly distilled ether in a tin vessel half full, the inner surfaces of which have been mildly abraded to remove surface film or tarnish, and the vessels shaken 16 hours at a temperature of 100 F. The well-known ammonium thiocyanate-ferrous sulphate reaction was used with a set of standard colors to determine the peroxides, and Nesslers reagent with color standards was used to estimate the aldehyde.

In the case of hydroquinone, it was found that, at a concentration of 10* molar (11 mg./l.), twenty out of twenty-one samples passed the accelerated aging test with respect to peroxide, whereas, at a concentration of 10* molar 1.1 mg./l.) only ten out of fifty-two samples passed. The color test for aldehyde could not be read at 10 molar because hydroquinone at this concentration interferes with the test; but at a concentration of 10- molar nearly half of the samples failed. In each series of tests, samples of ether containing no preservatives were included to be certain that the conditions were such that untreated other would spoil during the sixteen-hour test period.

Three samples of ether containing diphenylamine at a concentration of 10* molar (1.7 mg./l.) and three samples containing the same compound at a concentration of 10" molar (0,17

ing/1.) were also prepared and tested. All six samples failed both the peroxide and aldehyde tests.

Three samples of ether containing cupric dimethyldithiocarbamate at a concentration of 5 10- molar (1.5 mg./l.) and three at 5 l0"' molar (0.15 mg/l.) were tested by the above procedure. At the end of the accelerated aging test it was found that all three samples at a concentration of 5X10 molar passed both the aldehyde and peroxide tests, while at a concentration of 5 10"' molar one sample passed the peroxide test. Three additional samples at a concentration of l.5 l' molar (0.46 rug/l.) passed both tests.

Example 2 Example 1 was repeated except the six samples of ether containing cupric diethyldithiocarbamate at a concentration of SXIO' molar (1.8 mg/l.) and forty-eight samples at a concentration of X10 molar (0.18 dig/l.) were employed. At a concentration of 5X10" molar, all samples passed both the aldehyde and peroxide tests, while at a concentration of 5X10 molar, thirty-six samples passed the aldehyde test and twenty samples passed the peroxide test.

Additional tests were conducted employing thirty samples of ether containing cupric diethyldithiocarbamate at a concentration of 2.5 molar (0.9 mg./l.). At this concentration, all samples passed the aldehyde and peroxide tests.

Example 3 Example 1 was repeated except that three samples of ether containing sodium diethyldithiocarbamate at a concentration of 10* molar (1.7 rng./ l.) and three samples at a concentration of 10- molar (0.17 mg./l.) were employed. At both these concentrations, all samples passed both the aldehyde and peroxide tests.

Example 4 Example 1 was repeated except that three samples of ether containing stannous diethyldithiocarbamate at a concentration of 5 10 molar (2.1 mg./l.) were employed. All samples passed both the aldehyde and peroxide tests.

Example 5 The preservative action of cupric diethyldithiocarbamate in ether was determined in long-term aging tests as follows:

Freshly distilled anhydrous (absolute) ether initially containing less than 0.05 p. p. m. peroxide and less than 2-3 p. p. m. aldehyde was employed in these tests. Solutions of the preservative compound in other were pre pared in the same manner as in the accelerated tests of Examples 14-. The analytical tests for peroxides and aldehydes were the same as those employed in the accelerated tests of Examples l4, and the limits of 0.2 p. p. m. of peroxide and 3 p. p. m. of aldehyde were retained.

One-pound containers having a lacquered interior were filled with ether containing cupric diethyldithiocarbamate at a concentration of 5 l0- molar (0.18 mg./l.) and stored at 100 1 Comparative samples containing hydroquinone at a concentration of 10- molar (1.1 rug/l.) and ether without any preservative compound were stored under the same conditions. After six months of storage, it was found that the unpreserved ether samples and hydroquinone-containing samples failed both the aldehyde and peroxide tests; whereas, all samples of ether containing cupric diethyldithiocarbamate passed both tests.

Example 6 Example 5 was repeated, except that samples of ether containing sodium diethyldithiocarbamate at aconcentration of 10* molar (0.16 mg./l.) were used. Hydroquinone-containing and unpreserved ether samples were employed, and one-pound cans having a lacquered interior were again used as the ether containers.

4 After six months of storage, it was found that the 'unpreserved ether samples and hydroquinone-containing samples failed both the aldehyde and peroxide tests. When tested at the same time, samples of ether containing sodium diethyldithiocarbamate passed both tests. Samples containing sodium diethyldithiocarbamate were then further tested at intervals following the six-month tests, and, at the expiration of a nineteen-month period, all of these samples continued to pass both the aldehyde and peroxide tests.

Example 7 Example 5 was repeated, except that samples of ether containing stannous diethyldithiocarbarnate at a concentration of 5 10-" molar (0.21 mg./l.) were used. Hydroquinone-containing and unpreservecl ether samples were employed, and one-pound lacquered cans were again used as the ether containers.

After six months of storage, it was found that the unpreserved ether samples and hydroquinone-containing samples failed both the aldehyde and peroxide tests. When tested at the same time, all samples of ether containing stannous diethyldithiocarbamate passed both tests. These samples still passed both the aldehyde and peroxide tests after twenty-eight months of storage.

Example 8 Example 5 was repeated except that five-pound lacquered containers were used. Samples of unpreserved ether were employed as controls.

After four months of storage, it was found that the unpreserved ether samples failed both the aldehyde and peroxide tests. When tested at the same time, all of the samples of ether containing cupric diethyldithiocarbamate passed both the aldehyde and peroxide tests, and all samples still passed both the aldehyde and peroxide tests after twenty-four months of storage.

Example 9 Example 5 was repeated except that samples of ether containing sodium diethyldithiocarbamate at a concentration of 3 10 molar (.005 mg./l.) in one-pound containers having an interior coating of copper-tin oxide were used. Samples of unpreserved ether were employed as controls.

After six months of storage, it was found that the unpreserved ether samples failed both the aldehyde and peroxide tests. When tested at the same time, all of the samples of ether containing sodium diethyldithiocarbamate passed both tests.

It is to be understood that cupric, sodium and stannous dimethyldithiocarbamate and the corresponding diethyldithiocarbamates are of comparable utility in ether preservation.

Thus, the ether preservatives of the present invention when tested according to the accelerated aging tests are many times (e. g., ten to one hundred) more elfective in preserving ether than hydroquinone as determinedby standards higher than those required by the U. S. Pharmacopoeia. Moreover, when tested in dilferent types of ether containers for long periods of time under actual storage conditions, the preservative compounds of the invention effect between a seven and twenty-two months increase in the keeping time of ether over that attainable by the use of hydroquinone preservative or no preservative, and where a copper-tin oxide coated can, for example, is employed as a container, a concentration of preservative compound as low as 3X10" molar is effective to preserve ether for extended periods of time.

In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As various changes could be made in the above methods and products without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as i1- lustrative and not in a limiting sense.

We claim:

1. A composition comprising a substantial proportion of ether and a compound selected from the group consisting of cupric dimethyldithiocarbamate, cupric diethyldithiocarbamate, sodium dimethyldithiocarbamate, sodium diethyldithiocarbamate, stannous dimethyldithiocarbamate and stannous diethyldithiocarbamate as a preservative.

2. A composition comprising a substantial proportion of ether and cupric dimethyldithiocarbamate as a preservative.

3. A composition comprising a substantial proportion of ether and sodium dimethyldithiocarbamate as a preservative.

4. A composition comprising a substantial proportion of ether and cupric diethyldithiocarbamate as a preservative.

5. A composition comprising a substantial proportion of ether and sodium diethyldithiocarbamate as a preservative.

6. A composition comprising a substantial proportion of ether and stannous diethyldithiocarbamate as a preservative.

7. The method of preserving ether which comprises dissolving therein a compound selected from the group consisting of cupric dimethyldithiocarbamate, cupric diethyldithiocarbamate, sodium dimethyldithiocarbamate, sodium diethyldithiocarbamate, stannous dimethyldithiocarbamate and stannous diethyldithiocarbamate.

8. The method of preserving ether which comprises confining in an air-tight container ether having dissolved therein a compound selected from the group consisting of cupric dimethyldithiocarbamate, cupric diethyldithiocarbamate, sodium dimethyldithiocarbamate, sodium diethyldithiocarbamate, stannous dimethyldithiocarbamate and stannous diethyldithiocarbamate.

9. The method of preserving ether which comprises confining in an air-tight container ether having dissolved therein cupric dimethyldithiocarbamate.

10. The method of preserving ether which comprises confining in an air-tight container ether having dissolved therein sodium dimethyldithiocarbamate.

11. The method of preserving ether which comprises confining in an air-tight container ether having dissolved therein cupric diethyldithiocarbamate.

12. The method of preserving ether which comprises confining in an air-tight container ether having dissolved therein sodium diethyldithiocarbamate.

13. The method of preserving ether which comprises confining in an air-tight container ether having dissolved therein stannous diethyldithiocarbamate.

References Cited in the file of this patent UNITED STATES PATENTS 2,354,632 Wolfram et a1. July 25, 1944 OTHER REFERENCES Sandell: Chem. Absts., vol. (1951), col. 815. 

1. A COMPOSITION COMPRISING A SUBSTANTIAL PROPORTION OF ETHER AND COMPOUND SELECTED FORM THE GROUP CONSISTING OF CUPRIC DIMETHYLDITHIOCARBAMATE, CUPRIC DIETHYLDITHIOCARBAMATE, SODIUM DIMETHYLDITHIOCARBAMATE, SODIUM DIETHYLDITHIOCARBAMATE, STANNOUS DIMETHYLDITHIOCARBAMATE AND STANNOUS DIETHLDITHIOCARBAMATE AS A PRESERVATIVE.
 8. THE METHOD OF PERSERVING ETHER WHICH COMPRISES CONFINING IN AN AIR-TIGHT CONTAINER ETHER HAVING DISSOLVED THEREIN A COMPOUND SELECTED FROM THE GROUP CONSISTING OF CUPRIC DIMETHYLDITHIOCARBAMATE, CUPRIC DIETHYLDITHIOCARBAMATE, SODIUM DIMETHYLDITHIOCARBAMATE, SODIUM DIETHYLDITHIOCARBAMATE, STANNOUS DIMETHYLDITHIOCARBAMATE AND STANNOUS DIETHYLDITHIOCARBAMATE. 